Our research has been focused on understanding host-pathogen interactions in infectious diseases especially sepsis, which are highly complex diseases that engage many of the body's systems, and where disease severity is modulated by genetic variability in both the host and the pathogen. In this proposal, we aim to understand how individual variations can drastically modulate severity and outcomes of sepsis caused by S. pyogenes, aka Group A streptococcus (GAS) bacteria, which are known to cause a wide spectrum of diseases, whose onset and manifestations are strongly influenced by host genetic variations. Accordingly GAS infections present an ideal model for studying mechanisms by which individual differences influence disease. Highly virulent strains of GAS re-emerged in the 1980s and were associated with the recrudescence of Streptococcal Toxic Shock Syndrome (STSS) and Necrotizing Fasciitis (NF; aka, the flesh-eating disease). Because we could recover the same virulent GAS strain (M1T1) from STSS cases as wel as frommild GAS bacteremia cases or even cases with mild pharyngitis, we proposed that host factors may be playing an important role in potentiating the outcomes of GAS sepsis. Indeed, our studies of a large cohort of patients with GAS sepsis who presented with different degrees of severity revealed that alelic variations in HLA-II was a major contributor to variations in disease outcomes. More recently we provided direct evidence that HLA-II variations play a pivotal role in conferring protection or increased risk for severe GAS sepsis and STSS. We also found that septic subjects expressing protective HLA-II alleles mount higher ratios of regulatory to inflammatory cytokines during the infection and experience mild bacteremia, and those with high risk HLA-II alleles mount potent, unregulated inflammatory responses and experience severe sepsis. In Aim 1, we will dissect molecular and cellular mechanisms underlying the differential polarization of immune responses to the same pathogen in individuals who bear protective vs. the high-risk HLA-II alleles, and how these differences may influence sepsis outcomes. To understand the basis for differences in disease outcomes among individuals, who neither carry protective nor high-risk HLA-II alleles, we took advantage of a novel mouse model of Advanced Recombinant Inbred (ARI) mice, which are ideally suited for systems genetics and systems biology approaches. Data from this model have helped us locate regions on mouse chromosomes that harbor genes with a high statistical likelihood of being engaged in modulating sepsis severity and outcomes. In Aim 2, we will verify the role of mapped genes in potentiating GAS sepsis severity, and dissect mechanisms by which complex interactions among different sets of disease associated polymorphic genes in genetically distinct subjects influences disease severity and manifestations. Data from both models are complementary and will provide insight into interactive networks of host response pathways engaged in this complex disease of sepsis, as wel as reveal pathways that may be targeted to ameliorate disease severity in individuals who are genetically predisposed to STSS. PUBLIC HEALTH RELEVANCE: Our research focuses on developing means by which to triage and treat infected subjects based on their risk level, as dictated by combinations of their genetic and soluble biomarkers. This knowledge may suggest optimal treatment modalities to allow the personalization of medical intervention and judicial allocation of scarce resources in cases of wide spread natural or deliberate biological threats. Specifically, we are combining reductionist and holistic systems approaches to elucidate the genetics of susceptibility to infectious disease, and gain a comprehensive understanding of mechanisms underlying host-pathogen interactions in serious infections. The proposed research focuses on elucidating how variations in host genetic context can drastically alter outcomes of sepsis caused by Group A streptococcal (GAS) bacteria. Knowledge gained from our GAS sepsis model continues to mold and impact the way we approach our investigation of mechanisms underlying differential outcomes in infections with select agents to develop more targeted and effective interventions.